| Project/Area Number |
17K08292
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Hoshi University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
今井 正彦 星薬科大学, 薬学部, 講師 (40507670)
長谷川 晋也 星薬科大学, 薬学部, 講師 (60386349)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | レチノイン酸 / レチノイル化 / タンパク質修飾 / シグナル伝達 / プロテインキナーゼA / ノンジェノミック / 蛋白質修飾 / 細胞分化 / がん |
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| Outline of Final Research Achievements |
Retinoic acid (RA) is an important nutrient that has been drawing attention from the viewpoint of prevention and treatment of cancer and lifestyle-related diseases etc. Using human leukemia cells, we investigated retinoylation (protein modification by RA), which is a non-genomic mechanism of action of RA that is different from nuclear receptors. We elucidated the physiological roles of the retinoylated proteins, RhoGDIβ, which regulates actin polymerization, α-actinin, an actin-binding protein and regulatory subunits of protein kinase A (PKA). We found that retinoylation stabilizes each protein and enhances their function. In addition, we provided evidence that retinoylation translocates PKA to the nucleus, promoting phosphorylation of nuclear proteins including histones that are important for gene expression regulation, and that it enhances histone catabolism. These findings help elucidate non-genomic mechanisms of RA action.
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| Academic Significance and Societal Importance of the Research Achievements |
RA修飾によるタンパク質の構造変化で安定性・局在性・酵素活性等が変わる点はRA受容体とは異なることから、レチノイル化は新しい情報伝達機構となる。本研究でレチノイル化がPKA、ヒストン、細胞骨格関連タンパク質の安定性に変化を与え、本来の機能を増大させ、RA作用を発現させることを示した。レチノイル化PKAを介するヒストンのリン酸化経路を基にレチノイル化ヒストン経路を実証し、RAによるエピジェネティクス制御作用という新規な概念を提案することは、従来のRA受容体経路を補完することを証明できるという学術的意義を与える。また、この新規経路を基にして、がんや生活習慣病の治療薬の開発が行える社会的意義を持つ。
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